Work was conducted under clinical protocols NCT03065335 and NCT03289923. Major accomplishments for the NNU were the recruitment of additional staff, continuing to acquire research data in our collaboration with the Experimental Therapeutics and Pathophysiology Branch (ETPB) and expanding that collaboration to a second study just launched, continuing our initial multimodal protocol in combined TMS and talk therapy, installation and testing of neuromodulation equipment including robotic coil placement for precision cortical targeting, expanding our training of staff to include additional labs at NIH as a core function, and continuing and expanding our healthy volunteer protocol for TMS tool development. We now have two fully functional noninvasive neuromodulation laboratories operating in the Clinical Center and are actively enrolling subjects in IRB approved trials. Training in the safe and effective delivery of neuromodulation is one of our major functions as a Service within the Center for Multimodal Neuroimaging. We continue to provide in-service training on TMS safety, including hands-on training sessions covering the following procedures: Motor threshold determination, electromyography (EMG), Neuronavigation, simultaneous TMS/EEG to measure TMS-evoked potentials, TMS-Safety procedures, and the role of Nursing in TMS and patient management. Our projects fall into 3 themes: 1) measuring neuroplasticity, 2) modulating neuroplasticity, 3) modeling the effects of neuromodulation and mining multi-modal datasets to discover biomarkers of rapid antidepressant response. Our projects include: Theme I: Measuring Neuroplasticity Mechanisms of Rapid Antidepressant Action collaboration with Drs. Zarate and Park o This project develops biomarkers of rapid antidepressant response through the addition of TMS-EMG, TMS-EEG neuroplasticity measures to the existing intramural research program on ketamine. Concurrent fMRI-guided rTMS and cognitive therapy for the treatment of major depressive episodes o This project (which also incorporates Theme II, below) uses MEG (in collaboration with Allison Nugent (ETPB)), fMRI, and TMS/EEG to measure brain network engagement and neuroplastic changes due to multimodal TMS/CBT in depressed adults. Theme II: Modulating Neuroplasticity We are taking complementary approaches to modulating neuroplasticity: 1) seizure-induced neuroplasticity, 2) paired associative stimulation (PAS) and 3) novel tool development to extend the spatial and temporal specificity of noninvasive neuromodulation. Next generation seizure therapy collaboration with Drs. Zarate, Park, Bikson, Datta o Therapeutically induced seizures exert rapid antidepressant action and are robust inducers of neurotrophic factors and neurogenesis. New technologies for focal seizure induction may improve the risk/benefit ratio by lowering cognitive side effects, and also provide the valuable scientific opportunity to examine common mechanisms across rapidly acting interventions such as ketamine. o This project involves optimization of seizure therapy dosing, through the study of individualized low amplitude seizure therapy (iLAST), comprised of focal seizure induction with minimal current exposure to improve tolerability of seizure therapy for depression. Cognitive Paired Associative Stimulation (C-PAS) o PAS has been shown to strengthen synaptic efficacy within a circuit through repeated co-activation and coincident firing. We extend that approach to activate a targeted neural circuit through cognitive task performance, and couple that with simultaneous focal neuromodulation to enhance plasticity, as a means of enhancing circuit function and improving the functional-specificity of neuromodulation action. One of our projects employs fMRI-guided TMS paired with a specific form of cognitive behavioral therapy for the treatment of depression (in collaboration with Dr. Strauman). Another of our projects, being conducted in the form of a cooperative agreement (5U01AG050618) uses fMRI-guided TMS with simultaneous working memory training to enhance executive function in older adults (in collaboration with Drs. Appelbaum, Peterchev, and Cabeza). Novel Tool Development TMS research has been slowed due to two fundamental problems that directly impact its usefulness. First, the space of parameters used to produce TMS is immensely large and has barely been explored. Second, the interaction of any set of TMS parameters with any individual brain is poorly understood, and this has led to unpredictable efficacy and a large amount of inter-individual variability in TMS studies. The purpose of this technical development protocol is to address these two fundamental deficiencies. Our ongoing projects within this healthy volunteer protocol include: 1. Controlling ongoing cortical state during NIBS with neurofeedback. This study asks: Does controlling brain states using neurofeedback result in greater intra- and inter-individual variability in responses to TMS? The aim is to explore the use of neurofeedback to control brain state, using EEG to evaluate the cortical response to single pulses of TMS while subjects are controlling the electrophysiological state of their brain. 2. Parametric studies to optimize theta-burst stimulation (TBS). While patterned stimulation such as TBS may represent a more potent form of TMS, its effects are quite unreliable between subjects. Moreover, there has not been a parametric examination of the stimulation parameters used in TBS. We have begun with the intertrain interval as the first parameter to examine, with the aim to parametrically measure its effects on TBS response. 3. Noninvasive focal deep brain stimulation (nfDBS) We seek to establish whether TMS can reach, in a dose-dependent way, a targeted subcortical region transynaptically which is too distant for effective direct TMS stimulation, using TMS as a probe of the fronto-striatal network, a key circuit implicated in reward processing. This will be tested with the perturbation-imaging procedure of TMS/fMRI interleaving, i.e. while participants receive TMS during both resting state and task-based fMRI. 4. Transcranial direct current stimulation to reduce effects of nicotine withdrawal syndrome NIDA Protocol 12-DA-N474 (PI: E.A.Stein, collaborators: Sarah Aronson) Symptoms of nicotine withdrawal remain a major impediment for smokers trying to quit, with most quit attempts failing within the first week of abstinence when withdrawal symptoms are at their height. Transcranial Direct Current Stimulation (tDCS) has the potential to modify neuronal circuits by application of a subthreshold conductive current through the scalp. The goal is to investigate the effects of tDCS on modulating large-scale brain networks dysregulated in nicotine addiction and withdrawal. 5. Closed-loop paired associative stimulation The effects of noninvasive brain stimulation can be extremely variable across subjects. One source of this variability is known to be the state of the brain at the time of stimulation. One way of addressing this source of variability is to trigger the TMS when the brain is in an up-state or a down-state. To accomplish this, real-time signal processing is utilized to analyze the EEG and predict where the brain oscillations will be milliseconds in advance. The TMS trigger is controlled by the real-time hardware. Theme III: Modeling Neuroplasticity / Mining Multi-Modal Datasets Our team comprises engineering expertise to perform in silico modeling of the spatial and temporal effects of neuromodulation on neuronal function, and to apply machine learning and graph theoretical approaches to data-mining and hypothesis generation to support the discovery of common mechanisms across rapidly acting antidepressant interventions.